DESCRIPTION (Applicant's abstract): The neuronal circuitry underlying respiratory rhythm genesis is a complex system with complex neuronal dynamics involving various neuronal populations within the mammalian brainstem. This rhythm persists in reduced in vitro preparations, including the en bloc brainstem-spinal cord and the transverse slice. While these reduced preparations have greatly advanced the study of respiratory rhythm genesis at the cellular level, the neuronal dynamics of even these reduced preparations are not completely understood. The objective of this particular application is to fully understand mechanisms for respiratory rhythm genesis in both in vitro and in vivo preparations; our particular approach is the use of computational models and quantitative data analysis techniques. We hypothesize that the aspiratory phase of the respiratory rhythm is generated by neurons in the pre-Botzinger complex (pBc) that display adaptive ion channel properties, and that this population interacts via excitatory and inhibitory connections with other respiratory regions to produce the complete respiratory rhythm in vivo. We further hypothesize that the nature of the excitatory synaptic connectivity within the pBc not only coordinates the aspiratory phase but also makes the respiratory rhythm more robust in the presence of cell-to-cell variability and external disturbances. Our specific aims are 1) determine how intrinsic ion channel properties and extrinsic synaptic input regulate burst frequency and duration and action potential firing rates of aspiratory pBc neurons; 2) determine how cellular heterogeneity and synaptic properties affect the synchronization and stability of the respiratory rhythm; and 3) determine the role of pacemaker-based and network-based modes of respiratory rhythm generation by extending our model to consider the en bloc brainstem spinal cord preparation. This research will increase our understanding of basic cellular and synaptic mechanisms underlying respiratory rhythm generation and may ultimately lead to new pharmacological techniques for clinical intervention and prophylaxis for such disorders as sudden infant death syndrome, sleep apnea and apnea of prematurity, central alveolar syndrome, and other forms of respiratory control failure.